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<p>Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. A significant portion of the alcohol-related differences in gene expression were accompanied by a corresponding difference in chromatin accessibility within the gene. We observed transcriptional differences in medium spiny neurons that impact RNA metabolism and immune response pathways. A small cluster of D1/D2 hybrid neurons showed AUD-induced differences distinct from the D1 and D2 types, suggesting a unique role in AUD. Those with AUD had a higher proportion of microglia in an inflammatory state; astrocytes entered a reactive state partially regulated by <i>JUND</i>. Oligodendrocyte dysregulation was driven in part by <i>OLIG2</i> activity and increased TGF-β1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1β pathway. These findings provide valuable insights into the genetic and cellular mechanisms in the caudate related to AUD. They also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.</p>

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Integrated single-cell multiomic profiling of caudate nucleus suggests key mechanisms in alcohol use disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月13日

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  • Nicholas C. Green,
  • Hongyu Gao,
  • Xiaona Chu,
  • Qiuyue Yuan,
  • Patrick McGuire,
  • Dongbing Lai,
  • Guanglong Jiang,
  • Xiaoling Xuei,
  • Jill L. Reiter,
  • Julia Stevens,
  • Greg T. Sutherland,
  • Alison M. Goate,
  • Zhiping P. Pang,
  • Paul A. Slesinger,
  • Ronald P. Hart,
  • Jay A. Tischfield,
  • Arpana Agrawal,
  • Yue Wang,
  • Zhana Duren,
  • Howard J. Edenberg,
  • Yunlong Liu

摘要

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. A significant portion of the alcohol-related differences in gene expression were accompanied by a corresponding difference in chromatin accessibility within the gene. We observed transcriptional differences in medium spiny neurons that impact RNA metabolism and immune response pathways. A small cluster of D1/D2 hybrid neurons showed AUD-induced differences distinct from the D1 and D2 types, suggesting a unique role in AUD. Those with AUD had a higher proportion of microglia in an inflammatory state; astrocytes entered a reactive state partially regulated by JUND. Oligodendrocyte dysregulation was driven in part by OLIG2 activity and increased TGF-β1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1β pathway. These findings provide valuable insights into the genetic and cellular mechanisms in the caudate related to AUD. They also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.